1. Field of the Invention
This invention relates to a pharmaceutical composition comprising at least a lactam antibiotic and at least an ion-chelating agent, which inhibits the formation of aggregates in the composition. Optionally, the pharmaceutical composition further comprises at least a β-lactamase inhibitor, or a buffer component, or at least a β-lactamase inhibitor and a buffer component. The pharmaceutical composition of the invention is stable in liquid form.
2. Description of the Related Art
Cephalosporins are derived from Cephalosporium bacteria. Among them, Cephalosprorin C is widely used due to its broad anti-bacterial spectrum and low toxicity. First, second, third, and fourth generations of semi-synthetic-β-lactam antibiotics have been developed though structure transformation of Cephalosprorin C. To date, β-lactam antibiotics account for about a half of all antibiotics used to fight microbial infections.
β-Lactam antibiotics inhibit the synthesis of bacteria cell wall by inhibiting the activity of the D-alanyl-D-alanine transpeptidase (peptidoglycan transpeptidase) inside bacteria. Peptidoglycans are linear polysaccharide polypeptides with a network structure alternately comprising N-acetyl-glucosamine (Glc-NAc) and Mur-NAc. The transpeptide cross-linking reaction of these linear polymers catalysed by peptidoglycan transpeptidase results in network architecture and completes cell wall synthesis. β-Lactam antibiotics irreversibly inhibit the activity of the peptidoglycan transpeptidase and cause a failure of bacterial cell wall formation. Without cell wall, bacterial cells don't have a definite shape and sustain high permeation pressure inside cells, which causes bacteriolysis resulting in the death of bacteria.
Bacteria have subsequently evolved to produce β-lactamase, which can hydrolyze the amido bond of the β-lactam ring of β-lactam antibiotics and transform β-lactam antibiotics into metabolites lacking antibacterial activity. In 1976, it was discovered that clavulanic acid separated from the fermented fluid of rod-like streptomycete was a unique β-lactamase inhibitor. Soon thereafter, other β-lactamase inhibitors, especially sulbactam and its lipid prodrugs, i.e., composition of ampicillin sodium and sulbactam sodium, and tazobactam became widely used in clinical settings.
Another type of antibiotics widely used is aminoglycoside antibiotics. Aminoglycoside antibiotics are glycosides formed from aminosugar (monosaccharide or disaccharide) and amino-cyclitol. They are alkaline in nature owing to their amino and other basic functional groups. Due to their broad anti-bacterial spectrum, high anti-bacterial activity, frequent clinical use, there have been more than 20 species of aminoglycosides developed since the discovery of the first aminoglycoside antibiotic, streptomycin, which was isulated from Streptothrix in 1940.
The anti-bacterial mechanism of action of aminoglycoside antibiotics is entirely different from that of β-lactam antibiotics. After entering bacteria the aminoglycoside antibiotic conjugates with the 30S subunit protein, which causes errors when tRNA translates mRNA code and results in non-functioning proteins inhibiting cell growth.
It is generally known that the combination of β-lactam antibiotics with aminoglycoside antibiotics provides an anti-bacterial synergy. However, β-lactam antibiotics are acidic whereas aminoglycoside antibiotics are basic. When these two types of antibiotics are dissolved in the same solution, either a salt precipitates out due to acid-base reaction, or the amino group of the aminoglycoside antibiotic reacts with the β-lactam group of the β-lactam antibiotics. Both of the reactions drastically reduce the efficacy of these types of antibiotics. Therefore, mixing of these two types of antibiotics in the same solution is normally disadvantageous.
A solution preparation of β-lactam antibiotics is not stable at room temperature. The solution forms aggregate particles, especially when a frozen preserved β-lactam antibiotics solution is thawed, or when a lyophilized powder preparation of β-lactam antibiotics is re-dissolved. In addition, the longer the solution stands, the more aggregate particles are generated. Aggregate particles in intravenous solution are harmful to the patient. Specifically, it has been found that infusion phlebitis is closely related to aggregate particle content in the infusion fluid (Remmington's Pharmaceutical Science, 18th Edition, Mark Publishing, 1990, p. 1567).
Further research has shown that when β-lactam antibiotics and aminoglycoside antibiotics are mixed in one solution, aggregate particles are more likely to occur. This has become another clinical problem that needs to be solved. A pharmaceutical composition, in which β-lactam antibiotics and aminoglycoside antibiotics can be stabilized while maintaining efficacy would be particularly beneficial in clinical use. Moreover, when a β-lactam antibiotic and an aminoglycoside antibiotic are combined in a mixture, the synergic bactericidal action can be achieved. This would have great social-economic significance.